Synovial cells in rheumatoid arthritis (RA) are regulated by a complex inflammatory environment. The long term goals of this project are to understand how signals from RA synovial factors are integrated to determine the phenotype and function of synovial myeloid lineage cells, including macrophages and osteoclasts. Macrophages play a key role in RA pathogenesis by production of cytokines that drive inflammation, and osteoclasts mediate pathologic bone resorption. Osteoclast differentiation is dependent on the TNF family member RANKL. During joint inflammation, inflammatory factors such as TNF and IL-1 increase osteoclast differentiation leading to increased bone resorption that is a major contributor to morbidity in RA. The inflammatory synovial environment also activates homeostatic mechanisms to limit joint damage associated with inflammation. However, the factors that restrain osteoclastogenesis during synovial inflammation and their mechanisms of action are poorly understood. Our overarching hypothesis is that augmenting homeostatic mechanisms that suppress bone resorption represents an effective therapeutic approach to decrease joint damage associated with RA. Therefore, we have set out to determine which factors present during synovitis are capable of suppressing osteoclastogenesis, and to determine their mechanisms of action. We have found that fibrin(ogen) and immune complexes, two factors expressed at high levels in RA synovium and implicated in inflammatory pathogenesis, suppress osteoclastogenesis. Fibrinogen activates signaling via 2 integrins and immune complexes ligate Fc receptors. This finding was surprising, as 2 integrins and Fc receptors signal via immunoreceptor tyrosine-based activation motif (ITAM)-mediated pathways that have previously been implicated in promoting osteoclast differentiation by providing costimulatory signals required for effective RANK responses. In addition, we have found that ITAM- mediated inhibitory signaling was defective in RA macrophages, suggesting that disease-related alterations in ITAM signaling compromise homeostatic mechanisms that normally restrain osteoclastogenesis in acute nonpathological inflammatory settings. Our findings lead us to hypothesize that ITAMs can deliver both positive and negative signals for osteoclastogenesis, and that manipulation of the balance of these signals therapeutically can be used to suppress inflammatory bone resorption in RA. In this application, we will investigate molecular mechanisms and pathways by which fibrinogen and immune complexes inhibit osteoclastogenesis. We will predominantly use human systems that are directly relevant for RA pathogenesis. We will also perform translational experiments with RA samples. We anticipate that our studies will provide insights that can be utilized to modulate the balance of activating and suppressive ITAM-mediated signaling therapeutically to suppress inflammatory osteolysis in RA.